Myocardial infarction (MI) is a major cause of HF. MI requires persistent activation of the sympathetic adrenergic system (SAS) in order to maintain the pump function of the heart. SAS activation causes excessive activation of protein Kinase A (PKA) and Ca2+/calmodulin-dependent kinase II (CaMK II), which causes adverse cardiac remodeling and promotes HF development. Thus, limiting excessive PKA activity could have beneficial effects in hearts after MI. There are endogenous PKA inhibitor proteins (PKI) in the heart that may regulate PKA activity. However, the role of PKI in normal and diseased hearts remains unclear. We have found that the endogenous PKIa is upregulated in mouse hearts after MI and PKIa deficiency enhances cardiac adrenergic responses but precipitates HF development after MI. beta-AR stimulation also activates PKA- independent cardioprotective signaling pathways because: (1) PKA inhibition spares cAMP signaling to EPAC/Rap1/Raf/ERK pathway to protect cultured myocytes from apoptosis~ (2) PKI-GFP transgenic mice had improved cardiac function and reduced hypertrophy than control mice after MI. (3) Metoprolol, a beta-blocker may reduce some of beneficial effects of PKI in post-MI hearts. In this study we will determine if and how KI regulates adrenergic signaling in the normal and infarcted heart. We hypothesize that PKI-mediated inhibition of excessive PKA activation in stressed hearts will reduce the potentially detrimental effects of PKA and CaMK II signaling and will preserve beneficial effects f SAS signaling through cAMP/EPAC and b2AR/Gi/Akt pathways. Our hypothesis is that PKA is an essential nodal control point for the detrimental effects of excessive SAS activity i cardiac stress states. We predict that clinically effective bAR antagonists used to tret HF patients will probably reduce both detrimental and cardioprotective features of bAR signaling. Therefore, a selective PKA inhibitory approach through PKI will mimics an optimized biased beta-blocker, which may provide more benefit than commonly used beta-blocker therapies. To test these ideas, we have established a PKIa knockout mouse line, and transgenic mouse lines overexpressing different levels (high, medium and low) of a PKI-GFP fusion gene. To explore the role of EPAC activation in cardiac protection spared by PKA inhibition after MI, we will use mice deficient in EPAC1 or EPAC2. Our SPECIFIC AIMS are: 1. To determine the role of endogenous PKA inhibition by PKI in HF development after MI. PKI-a knockout and control mice will be stressed with MI. 2. To determine if and how selective inhibition of PKA, with overexpression of a PKI minigene (either by genetic manipulation or alternatively by viral gene delivery), can reduce MI-induced structural and functional changes that cause HF. We will also compare the protective effects of PKA inhibition with PKI to those of beta-blockers. Our long-term goal is to reveal the roles of PKA/PKI in HF and explore the possibility of using PKI to treat HF.